Botulism is a life-threatening, flaccid paralysis caused by a neurotoxin produced by the anaerobic bacterium Clostridium botulinum. The disease typically results from ingestion of pre-formed toxin present in contaminated food (Dowell (1984) Rev. Infect. Dis. 6(Suppl. 1): S202-S207), from toxin produced in vivo from infected wounds (Weber (1993) Clin. Infect. Dis., 16: 635-639, in the intestines of infants (Amon (1992) in Textbook of pediatric infectious diseases, R. D. Feigen and J. D. Chemy (ed.), 3rd ed., Saunders, Philadelphia, Pa.), or occasionally in adults.
In severe cases, patients require prolonged hospitalization in an intensive-care unit and mechanical ventilation. Specific therapy consists of administration of botulism antitoxin trivalent (equine) (Tacket et al. Am. J. Med., 76: 794-798); however, this product has a high incidence of side effects, including serum sickness and anaphylaxis (Black, et al. (1980) Am. J. Med., 69: 567-570). To avoid these side effects, human BIG has been produced from immunized volunteers and its efficacy is being determined in a prospective randomized trial in infants with botulism (Amon (1993) pages 477-482 in Botulinum and tetanus neurotoxins: neurotransmission and biomedical aspects, B. R. DasGupta (ed.), Plenum, New York, N.Y.). While theoretically nontoxic, human BIG also has limitations, largely related to production issues. These include potential transmission of blood-borne infectious diseases, variability in potency and specificity between lots, and the need to immunize humans. The latter issue has taken on increased importance with the use of BoNTs for the treatment of a range of neuromuscular diseases (Jankovic et al. (1994) Therapy with botulinum toxin. Marcel Dekker, New York, N.Y.; Moore (1995) Handbook of botulinum toxin treatment, Blackwell Science, Oxford, United Kingdom) Immunization of volunteers for production of BIG would deprive them of subsequent botulinum therapy.
As an alternative to immune globulin, neutralizing monoclonal antibodies with defined potency and specificity could be produced in unlimited quantities. To date, however, no efficacious neutralizing antibotulinum monoclonal antibodies have been produced (Middlebrook, et al. (1995) Curr. Top. Microbiol. Immunol. 195:89-122). Potential explanations for this failure include the following: (i) a neutralizing epitope(s) is less immunogenic than other epitopes; (ii) too few unique monoclonal antibodies have been studied; (iii) a toxoid immunogen (formaldehyde-inactivated crude toxin) that poorly mimics the conformation of the neutralizing epitope(s) has been used; and (iv) multiple epitopes must be blocked in order to achieve efficient neutralization (Lang, et al. (1993) J. Immunol. 151: 466-473).